Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study

Introduction Sorafenib is the only systemic therapy indicated to treat HCC 1 In two Phase III studies (SHARP and Asia-Pacific), sorafenib significantly improved OS in patients with uHCC 2-3 Pivotal studies generally included patients with preserved liver function Investigation of sorafenib in wider patient groups is needed 4 GIDEON is the largest prospective study in uHCC ever conducted Over 3000 patients have been enrolled from 39 countries 5 1.NCCN Guidelines™: Hepatobiliary Cancers. Available at: Accessed: June 7, Llovet JM, et al. N Engl J Med. 2008;359(4): Cheng AL, et al. Lancet Oncol. 2009;10(1): Lencioni R, et al. Int J Clin Prac. 2010;64(8): Marrero JA et al. Abstract presented at AASLD 2011 Annual Meeting uHCC, unresectable hepatocellular carcinoma; OS, overall survival;

The GIDEON study: design and objectives The GIDEON) study is a large, global, prospective, non- interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. Primary objective: to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice conditions. Secondary objectives: evaluate the efficacy [OS, progression-free survival (PFS), time to progression (TTP), response rate and stable disease rate] of sorafenib; determine the duration of therapy according to various patient characteristics; evaluate methods of patient evaluation, diagnosis and follow-up; assess comorbidities and their influence on treatment and outcome in real-life practice rather than a controlled clinical trial setting and evaluate the practice patterns of the physicians involved in the care of these patients. Lencioni R, et al. Int J Clin Prac. 2010;64(8):

The GIDEON study: design and objectives Planned subgroup analyses conducted globally, regionally and by country will include: the impact of baseline characteristics on safety, particularly Child-Pugh B; the relationship between baseline characteristics and efficacy; the duration of sorafenib therapy and reasons for discontinuation; the effect of other treatments for HCC on outcome and the impact of different practice patterns on outcome. Lencioni R, et al. Int J Clin Prac. 2010;64(8):

The GIDEON study: Patient eligibility Eligibility criteria include: Patients with histologically or cytologically documented or radiographically diagnosed unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib life expectancy of > 8 weeks Have provided signed informed consent. Lencioni R et al. Int J Clin Pract 2010;64:1034–4

Data are collected at the start of sorafenib treatment, then at intervals normally used by the prescribing physician, until death, withdrawal of consent, or until the patient is lost to follow-up The GIDEON study: Patient assessment schedule Lencioni R et al. Int J Clin Pract 2010;64:1034–41 Visit at entry Initial visit to start sorafenib Demografic data Past medical history Comitant disease Liver function ECOG PS History of HCC Initial stage Actiology Previous treatment Specilaity of the investigator and previous physician(s) Baseline data Current stage Weight BP ECOG PS Child-Pugh Sorafenib Initial dose Reason for treatment Follow-up during treatment with sorafenib Follow-up visit Tumor Weight BP ECOG PS Child-Pugh AE Sorafenib Given dose Evaluation DC of sorafenib Sorafenib Given dose Reason for DC Evaluation Concomitant Treatment for HCC for others Concomitant Treatment for HCC for others Follow-up after DC of Sorafenib Follow-up visit Tumor Weight BP ECOG PS Child-Pugh Death or Final visit Follow-up Oservation Survival status Tumor Weight BP ECOG PS Child-Pugh Reason for DC of observation Treatment for HCC Treatment for HCC Applicable if patient discontinues therapy, is alive and not lost to follow-up AE, adverse event; BP, blood pressure; DC, discontinuation: ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma Follow-up visit Tumor Weight BP ECOG PS Child-Pugh AE

Safety Adverse events Relation Seriousness NCI-CTC grade Action taken Outcome Child-Pugh score ECOG PS Efficacy OS TTS PFS RR SD Treatment for HCC Sorafenib therapy Duration of treatment Reason for discontinuation Other therapies Prior Concurrent Following Sorafenib Baseline characteristics History of HCC Duration from initial diagnosis Disease extent Stage (BCLC, TNM, CLIP) Tumor burden, presence of metastasis Previous treatment Aetiology Liver disorders Child-Pugh, cirrhosis ECOG PS Age, gender, race Co-morbidities The GIDEON study: safety, efficacy, treatment and baseline patient assessments and end-points Lencioni R et al. Int J Clin Pract 2010;64:1034–41 BCLC, Barcellona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program; ECOG, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; NCI-CTC, National Cancer Institute-Common Toxicity Criteria; OS, overall survival; PFS, progressio-free survival; RR, rensponse rate; SD, stable disease; TNM, tumor node metastases; TTP, time to progression

GIDEON study: regional distribution of patients Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

The GIDEON study: timeline and planned analyses Lencioni R et al. Int J Clin Pract 2010;64:1034–41 Phase I Objectives: Phase II Objectives: Phase III Objectives: Phase IV and V Objectives: Site initiation Study initiation Safety assessment in Child-Pugh B First interim analysis (500 patients) Second interim analysis (1500 patients) Safety assessment in Child-Pugh B Efficacy assessment of sorafenib in a board population of patients with HCC 3000 th patient Last patient’s last visit 31 December 2013 Analysis of final data - Safety - Efficacy Provide data to regolatory organizations

GIDEON final analysis patients population 3202 patients in the safety population Safety population used for analysis of AEs and serious AEs 3213 patients in the ITT population ITT population used for analysis of OS and TTP ITT, intent to treat; OS, overall survival; TTP, time-to-progression Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

% of n Child-Pugh A (n=1968) Child-Pugh B (n=666) Child-Pugh C (n=74) total (n=3202)* Number of patients Male/female82/1881/1982/18 Median age, years ECOG PS 0 or > TNM stage I5475 II III IV BCLC stage A8607 B22200 C D35895 *includes 493 non-evaluable patients BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, tumor node metastasis Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126) GIDEON final analysis: baseline patients characteristics by Child-Pugh status

GIDEON final analysis: overall treatment-emergent safety data by CP % of n Child-Pugh A (n=1968) Child-Pugh B (n=666) Child-Pugh C (n=74) total (n=3202) a AEs (all grades) Drug-related AEs (all grades) Serious AEs b (all grades) Drug-related serious AEs (all grades) All grade 3 or Drug-related grade 3 or AEs resulting in permanent discontinuation of sorafenib Deaths c Patients who received >1 dose of sorafenib and had >1 follow-up assessment were included in the safety analysis. a Includes 493 non-evaluable patients; b Any AE occurring at any dose that results in any of the following outcomes: death; life-threatening; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; c Treatment-emergent deaths occurring up to 30 days after last sorafenib dose Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

GIDEON final analysis: rate of drug-related AEs a by CP status Rate, event per patient-year a Child-Pugh A (n=1968) Child-Pugh B (n=666) Child-Pugh C (n=74) Total (n=3202) b Any AE Diarrhea HFSR Fatigue Rash / desquamation Anorexia Nausea Pain, abdomen, NOS Liver dysfunction a Rate calculation based on treatment-emergent AEs with >10% incidence and days per year; b Includes 493 non-evaluable patients Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

GIDEON final analysis: onset time of AEs > grade 3 by CP status  The onset time of AEs was comparable between Child-Pugh A and Child-Pugh B patients, with the majority of AEs occurring within the first 30 days of treatment in both groups Time to AE onset (days) Child-Pugh AChild-Pugh B Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

GIDEON final analysis: sorafenib dosing and treatment duration by CP status a Includes 493 non-evaluable patients Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126) Child-Pugh A (n=1968) Child-Pugh B (n=666) Child-Pugh C (n=74) total (n=3202) a Initial dose of 800 mg, % of Initial dose of 400 mg, % of n Median daily dose, mg Median treatment duration, weeks  Overall and across Child-Pugh subgroups, the majority of patients received the recommended initial dose of 800 mg  The median daily dose was similar across Child-Pugh subgroups  Duration of treatment was longer in Child-Pugh A patients than in Child-Pugh B patients

GIDEON final analysis: duration of sorafenib treatment by CP status Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)  Overall, the majority of patients received sorafenib for either,8 weeks (29.5%) or >24 weeks (35.9%), and 31.2% of patients received sorafenib for >28 weeks  In Child-Pugh B patients treated with sorafenib, 25.7% were treated for 24 weeks Duration of sorafenib treatment Child-Pugh AChild-Pugh B

GIDEON final analysis: OS by CP status CI, confidence interval Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126) Overall survival  Median overall survival (OS; months) was longer in Child-Pugh A patients than in Child-Pugh B and C patients (13.6 vs 5.2 and 2.6, respectively)

GIDEON final analysis: TTP by CP status Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)  Time to progression (TTP) was comparable between Child-Pugh A and B patients Time to progresion The imaging examination interval was at the investigators’ discretion

GIDEON final analysis: OS by Child-Pugh B score Overall survival  Median OS was shorter in patients with a higher Child-Pugh B score Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126)

Conclusions Marrero J, et al. J Clin Oncol 31, 2013 (suppl; abstr 4126) The safety profile of sorafenib in uHCC patients appears consistent, irrespective of liver function  AEs observed across Child-Pugh subgroups were in keeping with the known AE profile of sorafenib Child-Pugh status does not appear to influence the approach to sorafenib dosing, although duration of treatment is shorter in Child-Pugh B patients than in Child-Pugh A patients  Discontinuation of sorafenib due to AEs is higher in Child-Pugh B patients Consistent with previous reports, Child-Pugh status is a strong prognostic factor for OS in uHCC patients, regardless of treatment with sorafenib  TTP was similar in Child-Pugh A and Child-Pugh B patients, while OS was longer in Child-Pugh A patients